Switching from Axon Extension to Branching

Understanding the signaling pathways that enable neurons, such as dorsal root ganglion neurons, to extend axons into the periphery can identify potential therapeutic targets to promote nerve regeneration after injury. Miyamoto et al. found that the guanine nucleotide exchange factor Dock6, which regulates the cytoskeleton, was required for axonal extension during development and after nerve crush injury. Phosphorylation of Dock6 by the kinase Akt inhibited its activity; dephosphorylation by the phosphatase PP2A promoted Dock6 activity. During development, peripheral sensory neurons extend axons until the axons contact their targets, at which point they branch. During developmental stages when axons were growing, extending periods were associated with the interaction of PP2A with Dock6 and low Dock6 phosphorylation, whereas periods of branching were associated with the interaction of Akt with Dock6 and high Dock6 phosphorylation. Rescue experiments indicated that the phosphorylation status of Dock6 switched dorsal root ganglion neurons from axon extension to branching. Thus, regulation of the phosphorylation status of Dock6 by Akt and PP2A determines whether it promotes axon extension or branching in dorsal root ganglion neurons, and timing of treatments targeting this pathway for nerve regeneration is essential to proper reinnervation.